The goal of this proposal is to implement new strategies in personalized risk assessment for heart failure progression and sudden cardiac death (SCD) using a sequential algorithm involving ECG and cardiac MRI analyses in combination with conventional and newly emerging risk-stratification methods. While prevention of heart failure progression and SCD in patients of indeterminate risk represents one of the most challenging issues in contemporary cardiology, there has been little progress in reducing the incidence of heart failure and SCD mortality. Furthermore, current risk-stratification methods that focus on LV dysfunction and electrophysiological metrics lack the sensitivity and specificity needed for individualized care. Here we assess myocardial damage by applying novel automated ECG based QRS scoring combined with the detection of heterogeneity in myocardial structure and viability with contrast-enhanced MRI. We have validated the ECG QRS-scoring algorithm against high resolution scar quantification by MRI, thus demonstrating its potential utility in identifying individuals who should undergo detailed infarct heterogeneity studies by MRI for further risk stratification. Thus, in Phase I we apply the two modalities sequentially in combination with existing markers to refine development of an algorithm that will then be used to address feasibility and accuracy of the approach in a large (n>2,000) multi-center analysis during Phase II, where technological, logistical and intellectual advances refined in Phase I will be implemented at 4 additional institutions. Marker associations, cardiac events and statistical outcomes will be analyzed via the centralized computer system provided by the NIH Cardiovascular Research GRID resource (CVRG) at our institution. Based on preliminary data, we anticipate that this new combined diagnostic approach will discriminate patients who harbor previously undetected high risk for heart failure progression as well as SCD mortality susceptibility that is not detectable using current strategies. Evaluation of ancillary genetic- and bio-markers during Phase II will provide additional prognostic information useful for individualized risk assessment. RELEVANCE (See instructions): This proposal addresses two major public health challenges in cardiology: improved identification and risk stratification of patients for 1) sudden cardiac death and 2) heart failure progression and mortality. Focus is placed on non-invasive approaches relevant to evaluation of specific individuals to improve drug and device targeting using new and existing therapies.